This invention relates to compositions containing polyphenols, for example, cocoa polyphenols such as procyanidins in combination with at least one cholesterol lowering agent and methods for improving vascular health including treating and preventing atherosclerosis and cardiovascular disease.
Coronary artery disease, the primary form of cardiovascular disease (CVD), is the major cause of death in the United States today. Cerebrovascular disease is the third. The etiology of both coronary artery and cerebrovascular diseases is attributed to atherosclerosis. Through its clinical manifestations, atherosclerosis is the major cause of the more than one million heart attacks, approximately 400,000 strokes that occur each year and numerous vascular circulation problems. Many patients suffer from hypertension.
A substantial body of evidence has established a causal relationship between hypercholesterolemia and premature atherosclerosis; the higher the levels of plasma cholesterol, the greater the risk of subsequent heart attack. (see e.g. Steinberg, D., JAMA 264:3047 (1990)). In the chain of events leading to atherosclerosis, it is believed that the initiating event is the formation of xe2x80x9cfatty streaksxe2x80x9d in carotid, coronary, and cerebral arteries, and in the aorta. These lesions include fatty deposits of cholesterol and cholesteryl ester that are found principally within the smooth muscle cells and macrophages of the intimal layer. The migration and proliferation of vascular smooth muscle cells play a crucial role in the pathogenesis of atherosclerosis following the initial deposition of lipid.
Additionally, the development of atheroslerosis and cardiovascular disease are modulated by, and/or associated with, LDL oxidation, cyclo-oxygenase (COX) activity, lipoxygenase (LOX) activity, nitric oxide (NO) production, and nitric oxide synthase (NOS) activity. The relationships among the various pathways and processes involved herewith are represented in FIG. 1 and are described in detail in the International Appl. No. PCT/US97/05693 published as WO 97/36497, the relevant portions of which are hereby incorporated herein by reference. Briefly, LDL oxidation is a critical step in the initiation of lesions (atheromas) which occur when macrophages take up oxidatively modified LDL and transform into so-called xe2x80x9cfoam cells.xe2x80x9d Enzymes COX and LOX are involved in arachidonic acid pathway which leads to the production of prostaglandins and thromboxane A2, the latter being known to cause vasoconstriction and platelet aggregation, and thus progression of atherosclerosis. Nitric oxide is known to inhibit platelet aggregation, monocyte adhesion/chemotaxis and proliferation of vascular smooth muscle all of which are considered to be responsible for progression of atherosclerosis. Cocoa polyphenols have been shown to have beneficial effects on the above-described processes by inhibiting LDL oxidation, enhancing NO/NOS activity and inhibiting COX/LOX activity. These effects are shown, for example, in the International Appl. No. PCT/US97/05693 published as WO97/36497 and the examples reported in the application. Cocoa polyphenols can be used to treat or prevent conditions which are known to be affected by the administration of non-steroidal anti-inflammatory drugs, for example, aspirin.
Despite the benefits of the cocoa polyphenol on the number of pathways and conditions associated with induction and progression of atherosclerosis and CHD, it has been found that these compounds do not have noticeable cholesterol lowering effect. Thus, the inventors have prepared an improved composition containing polyphenols in combination with at least one cholesterol lowering agent. The composition has enhanced effects on vascular health of a mammal, particularly a human, in comparison to the previously known compositions containing polyphenol or cholesterol lowering agents.
The invention relates to compositions and methods for improving vascular health in a mammal, a human or a veterinary animal in particular.
In one aspect, the invention relates to a composition, such as a food, a food additive, a dietary supplement, or a pharmaceutical comprising a cocoa polyphenol and a cholesterol lowering agent. The composition may optionally contain L-arginine.
In another embodiment, the invention relates to a cholesterol reducing confectionery, most preferably cholesterol reducing chocolates (e.g. dark chocolate) and confectionery containing cholesterol reducing chocolate.
In another aspect, the invention relates to a method for improving vascular health, including preventing or treating atherosclerosis and cardiovascular disease in a mammal, such as a human or a veterinary animal, by administering a composition containing a cocoa polyphenol and a cholesterol-reducing compound, and optionally L-arginine. Polyphenols from other sources having properties similar to those of cocoa polyphenols may also be used in the compositions and methods of the invention in combination with cholesterol lowering agents, such as sterol and/or stanol based cholesterol lowering agents.
In yet another embodiments, the invention relates to a method of enhancing absorption of a polyphenol, for example a flavanol or a flavonol by administering to a mammal the polyphenol in combination with a phytosterol and/or phytostanol. The compositions and products of manufacture for use in the method are also provided.